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Definitions

• the invention relates to novel benzamides which are used in the pharmaceutical industry for the production of medicaments.
• the international patent applications WO93/25517, WO95/01338 and WO96/03399 disclose trisubstituted phenyl derivatives as selective PDE4 inhibitors.
• the international patent applications WO94/02465 and WO95/20578 also describe 3- or polysubstituted phenyl derivatives as inhibitors of phosphodiesterase 4 and of TNF secretion.
• the invention thus relates to compounds of the formula I,
• R1 is 1-6C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, benzyloxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
• R2 is hydrogen
• R3 is hydrogen
• R2 and R3 are together a methylene group
• R4 is hydrogen, 1-8C-alkyl, 1-6C-alkoxy-1-4C-alkyl, 1-6C-alkylthio-1-4-alkyl, 1-6C-alkylsulfonyl-1-4C-alkyl, alkyl, 1-6C-alkylsulfonyl-1-4C-alkyl, 1-8C-alkylcarbonyl, 3-7C-cycloalkyl, 3-7C-cycloalkymethyl, phenyl-1-4C-alkyl or 1-4C-alkyl which is completely or predominantly substituted by fluorine,
• R5 is phenyl, pyridyl, phenyl substituted by R51, R52 and R53 or pyridyl substituted by R54, R55, R56 and R57, where
• R51 is hydroxyl, halogen, cyano, carboxyl, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, amino, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonylamino,
• R52 is hydrogen, hydroxyl, halogen, amino, trifluoromethyl, 1-4C-alkyl or 1-4C-alkoxy,
• R53 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
• R54 hydroxyl, halogen, cyano, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or amino,
• R55 is hydrogen, halogen, amino or 1-4C-alkyl
• R56 is hydrogen or halogen
• R57 is hydrogen or halogen
• n 1 or 2
• n 1 or 2
• 1-8C-Alkyl is straight-chain or branched alkyl radicals having 1 to 8 carbon atoms.
• Examples which may be mentioned are the octyl radical, isooctyl radical (6-methylheptyl radical), heptyl radical, isoheptyl radical (5-methylhexyl radical), hexyl radical, isohexyl radical (4-methylpentyl radical), neohexyl radical (3,3-dimethylbutyl radical), pentyl radical, isopentyl radical (3-methylbutyl radical), neopentyl radical (2,2-dimethylpropyl radical), butyl radical, isobutyl radical, sec-butyl radical, tert-butyl radical, propyl radical, isopropyl radical, ethyl radical and the methyl radical.
• 1-4C-Alkyl is straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl radical, isobutyl radical, sec-butyl radical, tert-butyl radical, propyl radical, isopropyl radical, ethyl radical and methyl radical.
• 1-6C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 6 carbon atoms.
• alkoxy radicals having 1 to 6 carbon atoms which may be mentioned are the hexyloxy radical, isohexyloxy radical (4-methylpentyloxy radical), neohexyloxy radical (3,3-dimethylbutoxy radical), pentyloxy radical, isopentyloxy radical (3-methylbutoxy radical), neopentyloxy radical (2,2-dimethylpropoxy radical), butoxy radical, isobutoxy radical, sec-butoxy radical, tert-butoxy radical, propoxy radical, isopropoxy radical, ethoxy radical and the methoxy radical.
• 3-7C-Cycloalkoxy is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
• 3-7C-Cycloalkylmethoxy is cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
• Examples of 1-4C-alkoxy which is completely or predominantly substituted by fluorine which may be mentioned are the 2,2,3,3,3-pentafluoropropoxy radical, the perfluoroethoxy radical, the 1,2,2-trifluoroethoxy radical in particular the 1,1,2,2-tetrafluoroethoxy radical, the 2,2,2-trifluoroethoxy radical, the trifluoromethoxy radical and preferably the difluoromethoxy radical.
• 1-6C-Alkoxy-1-4C-alkyl is one of the above-defined 1-4C-alkyl radicals which is substituted by a 1-6C-alkoxy radical. Examples which may be mentioned are the methoxymethyl radical, t-butoxymethyl radical, 1-ethoxyethyl radical and the 1-methyl-1-methoxyethyl radical.
• 1-6C-Alkylthio-1-4C-alkyl is a 1-4C-alkyl radical which is substituted by a 1-6C-alkylthio radical. Examples which may be mentioned are the methylthiomethyl radical and the tert-butylthiomethyl radical.
• 1-6C-Alkylsulfinyl-1-4C-alkyl is a 1-4C-alkyl radical which is substituted by a 1-6C-alkylsulfinyl radical.
• An example which may be mentioned is the methylsulfinylmethyl radical.
• 1-6C-Alkylsulfonyl-1-4C-alkyl is a 1-4C-alkyl radical which is substituted by a 1-6C-alkylsulfonyl radical.
• An example which may be mentioned is the methylsulfonylmethyl radical
• 1-8C-Alkylcarbonyl is a radical which, in addition to the carbonyl group, contains one of the abovementioned 1-8C-alkyl radicals.
• An example which may be mentioned is the acetyl radical, propanoyl radical and the butanoyl radical.
• 3-7C-Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
• 3-7C-Cycloalkylmethyl is a methyl radical which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals.
• the 3-5C-cycloalkylmethyl radicals cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl may be mentioned.
• Phenyl-1-4C-alkyl is one of the abovementioned 1-4C-alkyl radicals which is substituted by phenyl. Examples which may be mentioned are the phenethyl radical and the benzyl radical.
• Examples of 1-4C-alkyl which is completely or predominantly substituted by fluorine which may be mentioned are the 2,2,3,3,3-pentafluoropropyl radical, the perfluoroethyl radical, the 1,2,2-trifluoroethyl radical, in particular the 1,1,2,2-tetrafluoroethyl radical, the 2,2,2-trifluoroethyl radical, the trifluoromethyl radical and preferably the difluoromethyl radical.
• Halogen within the meaning of the invention is bromine, chlorine and fluorine.
• 1-4C-Alkoxycarbonyl is a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded. Examples which may be mentioned are the methoxycarbonyl radical (CH 3 O-C(O)—) and the ethoxycarbonyl radical (CH 3 CH 2 O-C(O)—).
• 1-4C-Alkylcarbonyloxy radicals in addition to the oxygen atom, contain one of the abovementioned 1-4C-alkylcarbonyl radicals.
• An example which may be mentioned is the acetoxy radical (CH 3 C(O)O—).
• Mono- or di-1-4C-alkylamino radicals in addition to the nitrogen atom, contain one or two of the abovementioned 1-4C-alkyl radicals.
• An example which may be mentioned is the dimethylamino radical.
• a 1-4C-alkylcarbonylamino radical which may be mentioned is the propionylamino radical (C 3 H 7 C(O)NH—) and the acetylamino radical (CH 3 C(O)NH—).
• phenyl radicals substituted by R51, R52 and R53 which may be mentioned are the radicals 2-acetylphenyl, 2-aminophenyl, 2-bromophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 4-diethylamino-2-methylphenyl, 4-bromo-2-trifluoromethylphenyl, 2-carboxy-5-chlorophenyl, 3,5-dichloro-2-hydroxyphenyl, 2-bromo-4-carboxy-5-hydroxyphenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl, 2,6-dibromophenyl, 2-cyanophenyl, 4-cyano-2-fluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2,6-dibro
• pyridyl radicals substituted by R54, R55, R56 and R57 which may be mentioned are the radicals 3,5-dichloropyrid-4-yl, 2,6-diaminopyrid-3-yl, 4-aminopyrid-3-yl, 3-methylpyrid-2-yl, 4-methylpyrid-2-yl, 5-hydroxypyrid-2-yl, 4-chloropyrid-3-yl, 3-chloropyrid-2-yl, 3-chloropyrid-4-yl, 2-chloropyrid-3-yl, 2,3,5,6-tetrafluoropyrid-4-yl, 3,5-dichloro-2,6-difluoropyrid-4-yl, 3,5-dibromopyrid-2-yl, 3,5-dibromopyrid-4-yl, 3,5-dichloropyrid-4-yl, 2,6-dichloropyrid-3-yl, 3,5-dii
• salts with bases are also suitable.
• examples of salts with bases which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, where here too the bases are employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
• Pharmacologically intolerable salts which can initially be obtained as process products, for example, in the preparation of the compounds according to the invention on an industrial scale are converted into pharmacologically tolerable salts by processes known to the person skilled in the art.
• the compounds according to the invention and their salts when they are isolated, for example, in crystalline form, can contain various amounts of solvents.
• the invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the formula I.
• R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
• R2 is hydrogen
• R3 is hydrogen
• R2 and R3 together are a methylene group
• R4 is hydrogen, 1-6C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylthio-1-4C-alkyl, 1-6C-alkylacarbonyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, phenyl-1-4C-alkyl or 1-4C-alkyl which is completely or predominantly substituted by fluorine,
• R5 is phenyl, pyridyl, phenyl substituted by R51, R52 and R53 or pyridyl substituted by R54, R55, R56 and R57, where
• R51 is halogen, cyano, carboxyl, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl,
• R52 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
• R53 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy
• R54 is halogen or 1-4C-alkyl
• R55 is hydrogen or halogen
• R56 is hydrogen or halogen
• R57 is hydrogen or halogen
• n 1 or 2
• n 1 or 2
• R1 is methoxy or difluoromethoxy
• R2 is hydrogen
• R3 is hydrogen
• R2 and R3 together are a methylene group
• R4 is hydrogen, 1-6C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylthio-1-4C-alkyl, 1-4C-alkylcarbonyl, phenethyl or benzyl,
• R5 is 2-bromophenyl, 2-chlorophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl, 2,6-dimethylphenyl, 2-chloro-6-fluorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methyl-pyrid-2yl, 2-chloropyrid-3-yl, 3-chloropyrid-4-yl, 3,5-dibromopyrid-2-yl, 3,5-difluoropyrid-4-yl, 2,3,5,6-tetrafluoropyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-dichloro-2,6
• n 1,
• n 1 and
• R1 is methoxy or difluoromethoxy
• R2 is hydrogen
• R3 is hydrogen
• R4 is hydrogen, 1-6C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylthio-1-4C-alkyl, 1-4C-alkylcarbonyl, phenethyl or benzyl,
• R5 is 2-bromophenyl, 2-chlorophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl, 2,6-dimethylphenyl, 2-chloro-6-fluorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methyl-pyrid-2yl, 2-chloropyrid-3-yl, 3-chloropyrid-4-yl, 3,5-dibromopyrid-2-yl, 3,5-difluoropyrid-4-yl, 2,3,5,6-tetrafluoropyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-dichloro-2,6
• n 1,
• n 1 and
• R1 is methoxy or difluoromethoxy
• R2 and R3 together are a methylene group
• R4 is hydrogen, 1-6C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylthio-1-4C-alkyl, 1-4C-alkylcarbonyl, phenethyl or benzyl,
• R5 is 2-bromophenyl, 2-chlorophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl, 2,6-dimethylphenyl, 2-chloro-6-fluorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloropyrid-3-yl, 3-chloropyrid-4-yl, 3,5-dibromopyrid-2-yl, 3,5-difluoropyrid-4-yl, 2,3,5,6-tetrafluoropyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-dichloro-2,6
• n 1,
• n 1 and
• Preferred compounds of the formula I are those in which
• R1 is methoxy or difluoromethoxy
• R2 is hydrogen
• R3 is hydrogen
• R2 and R3 together are a methylene group
• R4 is hydrogen, 1-4C-alkyl, 1-2C-alkoxy-1-2C-alkyl, 1-2C-alkylthio-1-2C-alkyl, 1-4C-alkylcarbonyl or benzyl,
• R5 is 3,5-dichloropyrid-4-yl, 2-chloropyrid-3-yl, 3-chloropyrid-4-yl, 3,5-dibromopyrid-2yl, 3,5-difluoropyrid-4-yl, 2,3,5,6-tetrafluoropyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-dichloro-2,6-difluoropyrid-4-yl or 2,6-dichloropyrid-3-yl,
• n 1,
• n 1 and
• R1 is methoxy or difluoromethoxy
• R2 is hydrogen
• R3 is hydrogen
• R4 is hydrogen, 1-4C-alkyl, 1-2C-alkoxy-1-2C-alkyl, 1-2C-alkylthio-1-2C-alkyl or benzyl,
• R5 is 3,5-dichloropyrid-4-yl, 2-chloropyrid-3-yl, 3-chloropyrid-4-yl, 3,5-dibromopyrid-2-yl, 3,5-difluoropyrid-4-yl, 2,3,5,6-tetrafluoropyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-dichloro-2,6-difluoropyrid-4-yl or 2,6-dichloropyrid-3-yl,
• n 1,
• n 1 and
• R1 is methoxy or difluoromethoxy
• R2 and R3 together are a methylene group
• R4 is hydrogen, 1-4C-alkyl or benzyl
• R5 is 3,5-dichloropyrid-4-yl, 2-chloropyrid-3-yl, 3-chloropyrid-4-yl, 3,5-dibromopyrid-2-yl, 3,5-difluoropyrid-4-yl, 2,3,5,6-tetrafluoropyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-dichloro-2,6-difluoropyrid-4-yl or 2,6-dichloropyrid-3-yl,
• n 1,
• n 1 and
• R1 is methoxy
• R2 is hydrogen
• R3 is hydrogen
• R2 and R3 together are a methylene group
• R4 is hydrogen, methyl, ethyl, methylthiomethyl or benzyl
• R5 is 3,5-dichloropyrid-4-yl
• n 1,
• n 1 and
• R1 is methoxy
• R2 is hydrogen
• R3 is hydrogen
• R4 is hydrogen, methyl, ethyl, methylthiomethyl or benzyl
• R5 is 3,5-dichloropyrid-4-yl
• n 1,
• n 1 and
• R1 is methoxy
• R2 and R3 together are a methylene group
• R4 is methyl or benzyl
• R5 is 3,5-dichloropyrid-4-yl
• n 1,
• n 1 and
• the compounds of the formula I are chiral compounds. Chiral centers occur on the carbon atoms bonded to the substituents (groups) R3 and OR4.
• the invention comprises both the pure enantiomers and their mixtures in any mixing ratio, including the racemates.
• the enantiomers can be separated in a known manner, for example by preparation and separation of corresponding diastereomeric compounds.
• the invention further relates to processes for the preparation of the compounds of the formula I and their salts, and also of the N-oxides of the pyridines and their salts.
• R1, R2, R3, R4, m and n have the meanings indicated above and X is a suitable leaving group, are reacted with amines R5-NH 2 , and in that, if desired, compounds of the formula I obtained are then converted into their salts and/or pyridines obtained are converted into the N-oxides and, if desired, then into the salts. or in that, if desired, salts of the compounds of the formula I obtained are then converted into the free compounds.
• the N-oxidation is carried out in a manner likewise familiar to the person skilled in the art, e.g. with the aid of m-chloroperoxibenzoic acid in dichloromethane at room temperature.
• the reaction conditions which are specifically necessary for carrying out the process are known to the person skilled in the art on the basis of his/her expert knowledge.
• the compounds of the formula II can be prepared according to the general reaction scheme 1.
• the alkylation is carried out in a suitable inert solvent such as DMF, THF or DMSO with addition of a base, preferably sodium hydride, and an alkylating reagent of the formula R4-Z, in which R4 has the meanings indicated above (exception R4 ⁇ H) and Z is a suitable leaving group.
• a suitable inert solvent such as DMF, THF or DMSO
• a base preferably sodium hydride
• the cyano group is then hydrolyzed to the carboxyl group (compounds of the formula III) in the compounds of the formula IV obtained by methods known to the person skilled in the art.
• the final activation of the carboxyl group (for example by conversion into an acid halide) yields the starting compounds of the formula II.
• the amines R5-NH 2 are known, or they can be prepared in a known manner.
• the reaction can be carried out, for example, in DMF as a solvent with addition of potassium carbonate as a base, preferably at elevated temperature.
• a suitable leaving group Y e.g. Y ⁇ Cl or Br
• Y a suitable leaving group Y
• the compounds of the formula XI obtained are then reacted with amines of the formula R5-NH 2 to give the compounds of the formula X.
• the preparation of the compounds of the formula X can also be carried out via the temporarily protected compounds of the formulae XIII, XIV and XV.
• the isolation and purification of the substances according to the invention is carried out in a manner known per se, for example by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on suitable support material.
• Salts are obtained by dissolving the free compound in a suitable solvent (e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low-molecular weight aliphatic alcohol such as ethanol or isopropanol), which contains the desired acid or base, or to which the desired acid or base is then added.
• the salts are obtained by filtration, reprecipitation, precipitation with a nonsolvent for the addition salt or by evaporation of the solvent. Salts obtained can be converted by alkalization or by acidification into the free compounds, which in turn can be converted into salts. In this way, pharmacologically intolerable salts can be converted into pharmacologically tolerable salts.
• m.p. stands for melting point
• d for day(s)
• h for hour(s)
• min for minute(s)
• RT room temperature.
• the invention preferably relates to the compounds mentioned in the examples and their salts.
• starting compound A4 700 mg (2.5 mmol) of 2,3-dihydro-4′7-dimethoxybenzofuran-2-spiro-3′-tetrahydrofuran-4-carboxylic acid (starting compound A4) are heated to reflux for 2 h in 10 ml of oxalyl chloride. Excess oxalyl chloride is removed in vacuo and coevaporated using 2 ⁇ 10 ml of toluene.
• the mixture is extracted with a total of 900 ml of ethyl acetate, the combined organic phases are dried over magnesium sulfate and concentrated.
• a suspension of 1.0 g (2.5 mmol) of N-(3,5-dichloropyridin-4-yl)-4-methoxy-3-pivaloyloxybenzamide (A17) in 5 ml of methanol is treated with 325 mg (6.0 mmol) of sodium methoxide in 5 ml of methanol and heated at 50° C. for 4 h. It is allowed to cool, concentrated, treated with 50 ml of water, acidified with 2 N hydrochloric acid and extracted with 4 ⁇ 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, concentrated and the crude product is crystallized from 20 ml of isopropanol. 870 mg of the title compound of m.p. 231-233° C. are obtained.
• the compounds according to the invention have valuable pharmacological properties which make them commercially utilizable.
• selective cyclic nucleotide phosphodiesterase (PDE) inhibitors namely of type 4
• they are suitable on the one hand as bronchial therapeutics (for the treatment of airway obstructions on account of their dilating but also on account of their respiratory rate- or respiratory drive-increasing action) and for the elimination of erectile dysfunction on account of the vasodilating action, but on the other hand especially for the treatment of disorders, in particular of inflammatory nature, e.g.
• the compounds according to the invention are distinguished here by low toxicity, good enteral absorption (high bioavailability), a large therapeutic breadth and the absence of significant side-effects.
• the compounds according to the invention can be employed in human and veterinary medicine as therapeu tics, where they can be used, for example, for the treatment and prophylaxis of the following illnesses: acute and chronic (in particular inflammatory and allergen-induced) airway disorders of various origins (bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD); dermatoses (especially of proliferative, inflammatory and allergic type) such as, for example, psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and wide-area pyodermias, endogenous and exogenous acne, acne
• disorders of the arthritis type rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions
• disorders of the immune system AIDS, multiple sclerosis
• graft-versus-host reactions transplant rejection reactions
• symptoms of shock [septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome and ARDS (adult respiratory distress syndrome)]
• generalized inflammations in the gastrointestinal area Crohn's disease and ulcerative colitis
• disorders of the heart which can be treated by PDE inhibitors, such as, for example, cardiac insufficiency, or disorders which
• the compounds according to the invention can be employed for the treatment of diabetes insipidus and disorders in connection with disturbances of brain metabolism, such as, for example, cerebral senility, senile dementia (Alzheimer's dementia), multiinfarct dementia or alternatively disorders of the CNS, such as, for example, depressions or arteriosclerotic dementia.
• brain metabolism such as, for example, cerebral senility, senile dementia (Alzheimer's dementia), multiinfarct dementia or alternatively disorders of the CNS, such as, for example, depressions or arteriosclerotic dementia.
• a further subject of the invention is a process for the treatment of mammals, including man, which are suffering from one of the abovementioned illnesses.
• the process comprises administering to the sick mammal a therapeutically efficacious and pharmacologically tolerable amount of one or more of the compounds according to the invention.
• the invention further relates to the compounds according to the invention for use in the treatment and/or prophylaxis of illnesses, in particular the illnesses mentioned.
• the invention likewise relates to the use of the compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the illnesses mentioned.
• Medicaments for the treatment and/or prophylaxis of the illnesses mentioned which contain one or more of the compounds according to the invention, are furthermore a subject of the invention.
• a further subject of the invention is a commercial product, consisting of a customary secondary pack, a primary pack containing the medicament (for example an ampoule or a blister pack) and, if desired, a pack insert, the medicament exhibiting antagonistic action against cyclic nucleotide phosphodiesterases of type 4 (PDE4) and leading to the attenuation of the symptoms of illnesses which are connected with cyclic nucleotide phosphodiesterases of type 4, and the suitability of the medicament for the prophylaxis or treatment of illnesses which are connected with cyclic nucleotide phosphodiesterases of the type 4 being indicated on the secondary pack or on the pack insert of the commercial product, and the medicament containing one or more compounds of the formula I according to the invention.
• the secondary pack, the primary pack containing the medicament and the pack insert otherwise comply with what would be regarded as standard to the person skilled in the art for medicaments of this type.
• the medicaments are prepared by processes which are known per se and familiar to the person skilled in the art.
• the compounds according to the invention are preferably also administered by inhalation.
• these are either administered directly as a powder (preferably in micronized form) or by nebulization of solutions or suspensions which contain them.
• a powder preferably in micronized form
• nebulization of solutions or suspensions which contain them are administered directly as a powder (preferably in micronized form) or by nebulization of solutions or suspensions which contain them.
• the compounds according to the invention are in particular used in the form of those medicaments which are suitable for topical application.
• suitable pharmaceutical formulations which may be mentioned are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions.
• the medicaments according to the invention are prepared by methods known per se. Dosage of the active compounds takes place in the order of magnitude customary for PDE inhibitors. Thus topical application forms (such as, for example, ointments) for the treatment of dermatoses contain the active compounds in a concentration of, for example, 0.1-99%.
• the dose for administration by inhalation is customarily between 0.1 and 3 mg per day.
• the customary dose in the case of systemic therapy (p.o. or i.v.) is between 0.03 and 3 mg per kilogram per day.
• the activation of inflammatory cells has particular importance.
• the FMLP N-formyl-methionyl-leucyl-phenylalanine
• the FMLP N-formyl-methionyl-leucyl-phenylalanine-induced superoxide production of neutrophilic granulocytes
• McPhail L C, Strum S L, Leone P A and Sozzani S The neutrophil respiratory burst mechanism.
• Coffey R G Marcel Decker, Inc. New York-Basle-Hong Kong
• Substances which inhibit chemoluminescence and cytokine secretion and the secretion of inflammatory mediators on inflammatory cells are those which inhibit PDE4.
• This isoenzyme of the phosphodiesterase families is particularly represented in granulocytes. Its inhibition leads to an increase in the intracellular cyclic AMP concentration and thus to the inhibition of cell activation.
• PDE4 inhibition by the substances according to the invention is thus a central indicator of the suppression of inflammatory processes (Giembycz MA, Can isoenzyme-selective phosphodiesterase inhibitors render bronchodilatory therapy redundant in the treatment of bronchial asthma?. Biochem Pharmacol 1992, 43, 2041-2051; Torphy T J et al., Phosphodiesterase inhibitors: new opportunities for treatment of asthma. Thorax 1991, 46, 512-523; Schudt C et al., Zardaverine: a cyclic AMP PDE 3 ⁇ 4 inhibitor.
• the activity test was carried out according to the method of Bauer and Schwabe, which was adapted to microtiter plates (Naunyn-Schmiedeberg's Arch. Pharmacol. 1980, 311, 193-198).
• the PDE reaction takes place in the first step here.
• the resulting 5′-nucleotide is cleaved by a 5′- nucloetidase of the snake venom of Crotalus atrox to the uncharged nucleoside.
• the nucleoside is separated from the remaining charged substrate on ion-exchange columns. The columns are eluted directly into minivials, into which 2 ml of scintillator fluid are additionally added, for counting using 2 ml of 30 mM ammonium formate (pH 6.0).
• inhibitory values determined for the compounds according to the invention [inhibitory concentration as -log IC 50 (mol/l)] follow from the following Table A, in which the numbers of the compounds correspond to the numbers of the examples.

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